Journal article
Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer
Clinical cancer research, v 30(2), pp 389-403
17 Jan 2024
PMID: 37939140
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE).
We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.
Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE.
Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.
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Details
- Title
- Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer
- Creators
- Joseph C Murray - Sidney Kimmel Comprehensive Cancer CenterLavanya Sivapalan - Sidney Kimmel Comprehensive Cancer CenterKarlijn Hummelink - The Netherlands Cancer InstituteArchana Balan - Sidney Kimmel Comprehensive Cancer CenterJames R White - Sidney Kimmel Comprehensive Cancer CenterNoushin Niknafs - Sidney Kimmel Comprehensive Cancer CenterLamia Rhymee - Sidney Kimmel Comprehensive Cancer CenterGavin Pereira - Sidney Kimmel Comprehensive Cancer CenterNisha Rao - Sidney Kimmel Comprehensive Cancer CenterBenny Weksler - Allegheny Health NetworkNathan Bahary - Allegheny Health NetworkJillian Phallen - Sidney Kimmel Comprehensive Cancer CenterAlessandro Leal - Sidney Kimmel Comprehensive Cancer CenterDavid L Bartlett - Allegheny Health NetworkKristen A Marrone - Sidney Kimmel Comprehensive Cancer CenterJarushka Naidoo - Sidney Kimmel Comprehensive Cancer CenterAkul Goel - California Institute of TechnologyBenjamin Levy - Sidney Kimmel Comprehensive Cancer CenterSamuel Rosner - Sidney Kimmel Comprehensive Cancer CenterChristine L Hann - Sidney Kimmel Comprehensive Cancer CenterSusan C Scott - Sidney Kimmel Comprehensive Cancer CenterJosephine Feliciano - Sidney Kimmel Comprehensive Cancer CenterVincent K Lam - Johns Hopkins UniversityDavid S Ettinger - Sidney Kimmel Comprehensive Cancer CenterQing Kay Li - Sidney Kimmel Comprehensive Cancer CenterPeter B Illei - Sidney Kimmel Comprehensive Cancer CenterKim Monkhorst - The Netherlands Cancer InstituteRobert B Scharpf - Sidney Kimmel Comprehensive Cancer CenterJulie R Brahmer - Sidney Kimmel Comprehensive Cancer CenterVictor E Velculescu - Sidney Kimmel Comprehensive Cancer CenterAli H Zaidi - Allegheny Health NetworkPatrick M Forde - Sidney Kimmel Comprehensive Cancer CenterValsamo Anagnostou - Sidney Kimmel Comprehensive Cancer Center
- Publication Details
- Clinical cancer research, v 30(2), pp 389-403
- Publisher
- American Association for Cancer Research (AACR)
- Grant note
- UG1 CA233259 / NCI NIH HHS P30 CA006973 / NCI NIH HHS P50 CA062924 / NCI NIH HHS R01 CA121113 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Surgery; General Internal Medicine
- Web of Science ID
- WOS:001154446300014
- Scopus ID
- 2-s2.0-85182614782
- Other Identifier
- 991021960799504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology